Sign up to receive free email alerts when patent applications with chosen keywords are publishedSIGN UP

2-(Butyl-1-sulfonylamino)-n-[1(R)-(6-methoxy-pyridin-3-yl)-propyl]-benzami- d, the use thereof in the form of drug an pharmaceutical preparations containing said compound - Patent applicationinit();
?>

Abstract:

The invention relates to
2-(butyl-1-sulfonylamino)-N-[1(R)-(6-methoxy-pyridin-3-yl)propyl]benzamid-
e of the formula I
##STR00001##
and to its pharmaceutically acceptable salts, their preparation and use,
in particular for the treatment and prophylaxis of atrial arrhythmias,
for example atrial fibrillation or atrial flutters.

Claims:

1-5. (canceled)

6. A compound wherein said compound is
1(R)-(6-methoxy-pyridin-3-yl)propylamine.

7. (canceled)

8. A process for the preparation of
2-(butyl-1-sulfonylamino)-N-[1(R)-(6-methoxypyridin-3-yl)propyl]benzamide
or a physiologically tolerable salt thereof, said process comprising the
steps of:providing 1(R)-(6-methoxypyridin-3-yl)propylamine; andcoupling
said 1(R)-(6-methoxypyridin-3-yl)propylamine with a sulfonylaminobenzoic
acid or a sulfonylaminobenzoic acid chloride.

9. The process according to claim 8, wherein said
1(R)-(6-methoxypyridin-3-yl)propylamine is coupled with
2-(butyl-1-sulfonylamino)benzoic acid.

10. The process according to claim 8, wherein said
1(R)-(6-methoxypyridin-3-yl)propylamine is coupled with
2-(butyl-1-sulfonylamino)benzoic acid chloride.

11. The process according to claim 9, wherein said coupling occurs in the
presence of a coupling reagent.

12. The process according to claim 11, wherein said coupling occurs in the
presence of 1-hydroxy-1H-benzotriazole and
N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0002]The invention relates to
2-(butyl-1-sulfonylamino)-N-[1(R)-(6-methoxypyridin-3-yl)propyl]benzamide
of the formula I, and to its pharmaceutically tolerable salts, their
preparation and use, in particular in medicaments.

##STR00002##

[0003]The compound of the formula I and its pharmaceutically tolerable
salts can reduce the occurrence of atrial arrhythmias without an action
on the heart chamber or other side effects occurring. The compound
according to the invention and its pharmaceutically tolerable salts are
therefore particularly suitable as a novel antiarrhythmic active
compound, in particular for the treatment and prophylaxis of atrial
arrhythmias, for example atrial fibrillation (AF) or atrial flutters.

[0004]Atrial fibrillation and atrial flutters are the most frequent,
lasting cardiac arrhythmias. The occurrence increases with advancing age
and frequently leads to fatal concomitant symptoms, such as, for example,
cerebral infarct. AF affects about 1 million Americans yearly and leads
to more than 80,000 strokes each year in the USA. The antiarrhythmics of
classes I and III customary at present reduce the reoccurrence rate of
AF, but are only used restrictively because of their potential
proarrhythmic side effects. There is therefore a great medical need for
the development of better medicaments for the treatment of atrial
arrhythmias (S. Nattel, Am. Heart J. 130, 1995, 1094-1106; "Newer
developments in the management of atrial fibrillation").

[0005]It has been shown that most supraventricular arrhythmias are subject
to "reentry" excitation waves. Such reentries occur when the cardiac
tissue possesses a slow conductivity and at the same time very short
refractory periods. The increase in the myocardial refractory period due
to prolongation of the action potential is a recognized mechanism for
ending arrhythmias or preventing their formation (T. J. Colatsky et al.,
Drug Dev. Res. 19, 1990, 129-140; "Potassium channels as targets for
antiarrhythmic drug action"). The length of the action potential is
essentially determined by the extent of repolarizing K.sup.+ currents
which flow out of the cell via various K.sup.+ channels. Particularly
great importance is ascribed here to the "delayed rectifier" IK, which
consists of 3 different components: IKr, IKs and IKur.

[0006]Most known class III antiarrhythmics (for example dofetilide, E4031
and d-sotalol) mainly or exclusively block the rapidly activating
potassium channel IKr, which can be detected both in cells of the
human ventricle and in the atrium. It has been shown, however, that these
compounds have an increased proarrhythmic risk at low or normal heart
rates, arrhythmias, which are described as "torsades de pointes", in
particular being observed (D. M. Roden, Am. J. Cardiol. 72, 1993,
44B-49B; "Current status of class III antiarrhythmic drug therapy").
Beside this high and in some cases fatal risk at a low rate, a decrease
in the activity under the conditions of tachycardia, in which the action
is needed in particular, was found for the IKr blockers ("negative
use dependence").

[0007]The "particularly rapidly" activating and very slowly inactivating
component of the delayed rectifier IKur (=ultra-rapidly activating
delayed rectifier), which corresponds to the Kv1.5 channel, plays a
particularly large part for the repolarization time in the human atrium.
An inhibition of the IKur potassium outward current thus represents,
in comparison to the inhibition of IKr or IKs, a particularly
effective method for the prolongation of the atrial action potential and
thus for the ending or prevention of atrial arrhythmias.

[0008]In contrast to IKr and IKs, which also occur in the human
ventricle, the IKur in fact plays an important part in the human
atrium, but not in the ventricle. For this reason, in the case of
inhibition of the IKur current in contrast to the blockade of
IKr or IKs, the risk of a proarrhythmic action on the ventricle
should be excluded from the start. (Z. Wang et al, Circ. Res. 73, 1993,
1061-1076: "Sustained Depolarisation-Induced Outward Current in Human
Atrial Myocytes"; G.-R. Li et al., Circ. Res. 78, 1996, 689-696:
"Evidence for Two Components of Delayed Rectifier K.sup.+ Current in
Human Ventricular Myocytes"; G. J. Amos et al., J. Physiol. 491, 1996,
31-50: "Differences between outward currents of human atrial and
subepicardial ventricular myocytes").

[0009]Antiarrhythmics which act via a selective blockade of the IKur
current or Kv1.5 channel have, however, not been available hitherto on
the market.

[0010]The enantiomer
2-(butyl-1-sulfonylamino)-N-[1(R)-(6-methoxypyridin-3-yl)-propyl]benzamid-
e claimed in this application has not been described hitherto. The
corresponding racemate is mentioned as an example in the patent
application WO 0288073. The compound of the formula I is distinguished by
surprising advantages.

[0011]It has now surprisingly been found that the antiarrhythmic action
for the 2-(butyl-1-sulfonylamino)-N-[1(R)-(6-methoxypyridin-3-yl)propyl]b-
enzamide of the formula I according to the invention is excellent in a
model on the anesthetized pig, while the corresponding 1(S) enantiomer is
more weakly active. It has furthermore been found that the compound of
the formula I has no effect on the QTc interval and no negative inotropic
or hemodynamic side effects.

[0012]The experiments confirm that the compound I can be used as a novel
antiarrhythmic having a particularly advantageous safety profile. In
particular, the compound is suitable for the treatment of
supraventricular arrhythmias, for example atrial fibrillation or atrial
flutters. The compound can be employed for the termination of existing
atrial fibrillation or flutters for the regaining of the sinus rhythm
(cardioversion). Moreover, it reduces the susceptibility to the formation
of new fibrillation events (retention of the sinus rhythm, prophylaxis).

[0013]The present invention relates to
2-(butyl-1-sulfonylamino)-N-[1(R)-(6-methoxypyridin-3-yl)propyl]benzamide
of the formula I, and to its pharmaceutically acceptable salts.

[0014]Since the compound I contains a basic pyridine radical, it can also
be used in the form of its pharmaceutically tolerable acid addition salts
with inorganic or organic acids, for example as a hydrochloride,
phosphate, sulfate, methanesulfonate, acetate, lactate, maleate,
fumarate, malate, gluconate etc. The sulfonamide group present moreover
makes possible the formation of alkali metal or alkaline earth metal
salts, preferably the sodium or potassium salt, or ammonium salts, for
example salts with organic amines or amino acids. The pharmaceutically
tolerable salts can be obtained from the compound of the formula I by
customary processes, for example by combination with an acid or base in a
solvent or dispersant or alternatively from other salts by anion or
cation exchange.

[0015]The free compound
2-(butyl-1-sulfonylamino)-N-[1(R)-(6-methoxypyridin-3-yl)propyl]benzamide
of the formula I is preferred.

[0016]The compound of the formula I can be prepared by different chemical
processes, of which two preparation possibilities are outlined in scheme
1. The coupling of the sulfonylaminobenzoic acid of the formula II with
the amine of the formula III can be carried out either directly from the
acid in the presence of a customary coupling reagent, or, for example,
from an activated acid derivative such as the acid chloride. When using
racemic 1-(6-methoxypyridin-3-yl)propylamine of the formula III, the
cleavage into the enantiomers takes place in the final stage, for example
by chiral chromatography or conventional resolution. Alternatively, the
desired enantiomer can be obtained directly by use of
1(R)-(6-methoxypyridin-3-yl)-propylamine of the formula IIIa. The
sulfonylaminobenzoic acid of the formula II is prepared in a manner known
to the person skilled in the art from the commercially obtainable
substances aminobenzoic acid and butylsulfonyl chloride.

##STR00003##

[0017]This application likewise includes the compound
1-(6-methoxypyridin-3-yl)-propylamine of the formula III employed as an
intermediate, and its enantiomers, in particular
1(R)-(6-methoxypyridin-3-yl)propylamine of the formula IIIa, and its use
for the preparation of pharmaceutical active compounds, for example of
2-(butyl-1-sulfonylamino)-N-[1(R)-(6-methoxy-pyridin-3-yl)propyl]benzamid-
e.

[0018]1-(6-Methoxypyridin-3-yl)propylamine of the formula III can be
prepared from commercially obtainable compounds by different chemical
processes, of which two preparation possibilities are outlined as
examples in scheme 2. On the one hand, 5-bromo-2-methoxypyridine can
firstly be metalated using butyllithium, then reacted with propionitrile
and subsequently reduced to the compound of the formula III using sodium
borohydride. Alternatively, 3-cyano-6-methoxypyridine can be reacted with
ethylmagnesium bromide and then reduced using sodium borohydride. The
cleavage into the enantiomers can be carried out by customary methods,
such as, for example, chromatography on a chiral phase, conventional
resolution with the aid of a chiral acid or by enzymatic methods.

##STR00004##

[0019]The compound of the formula I according to the invention and its
physiologically tolerable salts can be used on animals, preferably on
mammals, and in particular on humans, as a medicament on its own or in
the form of pharmaceutical preparations. The present invention also
relates to the compound of the formula I and its physiologically
tolerable salts for use as a pharmaceutical, its use in the therapy and
prophylaxis of cardiac arrhythmias, of supraventricular arrhythmias, of
atrial fibrillation and/or atrial flutters and its use for the production
of medicaments therefor. Furthermore, the present invention relates to
pharmaceutical preparations which as active constituent contain an
efficacious dose of the compound of the formula I and/or a
physiologically tolerable salt thereof in addition to customary,
pharmaceutically innocuous vehicles and excipients. The pharmaceutical
preparations normally contain 0.1 to 90 percent by weight of the compound
of the formula I and/or its physiologically tolerable salts. The
pharmaceutical preparations can be produced in a manner known to the
person skilled in the art. For this, the compound of the formula I and/or
its physiologically tolerable salts, together with one or more solid or
liquid pharmaceutical vehicles and/or excipients and, if desired, in
combination with other pharmaceutical active compounds, are brought into
a suitable administration form or dosage form, which can then be used as
a pharmaceutical in human medicine or veterinary medicine.

[0020]Pharmaceuticals which contain the compound of the formula I
according to the invention and/or its physiologically tolerable salts can
be administered, for example, orally, parenterally, e.g. intravenously,
rectally, by inhalation or topically, the preferred administration being
dependent on the individual case, for example the particular clinical
picture of the disease to be treated.

[0021]The person skilled in the art is familiar on the basis of his/her
expert knowledge with excipients which are suitable for the desired
pharmaceutical formulation. In addition to solvents, gel-forming agents,
suppository bases, tablet excipients and other active compound carriers,
it is possible to use, for example, antioxidants, dispersants,
emulsifiers, antifoams, taste corrigents, preservatives, solubilizers,
agents for achieving a depot effect, buffer substances or colorants.

[0022]To achieve an advantageous therapeutic action, the compound of the
formula I can also be combined with other pharmaceutical active
compounds. Thus, in the treatment of cardiovascular diseases
advantageous, combinations with substances having cardiovascular activity
are possible. Possible combination partners of this type advantageous for
cardiovascular diseases are, for example, other antiarrhythmics, that is
class I, class II or class III antiarrhythmics, such as, for example,
IKs or IKr channel blockers, for example dofetilide, or
furthermore hypotensive substances such as ACE inhibitors (for example
enalapril, captopril, ramipril), angiotensin antagonists and K.sup.+
channel activators, and alpha-receptor blockers, but also sympathomimetic
compounds and compounds having adrenergic activity, and Na.sup.+/H.sup.+
exchange inhibitors, calcium channel antagonists, phosphodiesterase
inhibitors and other substances having positive inotropic activity, such
as, for example, digitalis glycosides, or diuretics.

[0023]For an oral administration form, the active compound is mixed with
the additives suitable therefor, such as vehicles, stabilizers or inert
diluents, and brought by means of the customary methods into the suitable
administration forms, such as tablets, coated tablets, hard gelatin
capsules, aqueous, alcoholic or oily solutions. The inert carriers which
can be used are, for example, gum arabic, magnesia, magnesium carbonate,
potassium phosphate, lactose, glucose or starch, in particular corn
starch. The preparation can be carried out here both as dry and moist
granules. Suitable oily vehicles or solvents are, for example, vegetable
or animal oils, such as sunflower oil or cod-liver oil. Suitable solvents
for aqueous or alcoholic solutions are, for example, water, ethanol or
sugar solutions or mixtures thereof. Further excipients, also for other
administration forms, are, for example, polyethylene glycols and
polypropylene glycols.

[0024]For subcutaneous, intramuscular or intravenous administration, the
active compound, if desired with the substances customary therefor such
as solubilizers, emulsifiers or further excipients, is brought into
solution, suspension or emulsion.

[0025]The compound of the formula I and its physiologically tolerable
salts can also be lyophilized and the lyophilizates obtained used, for
example, for the production of injection or infusion preparations.
Suitable solvents are, for example, water, physiological saline solution
or alcohols, for example ethanol, propanol, glycerol, in addition also
sugar solutions such as glucose or mannitol solutions, or alternatively
mixtures of the various solvents mentioned.

[0026]Suitable pharmaceutical formulations for administration in the form
of aerosols or sprays are, for example, solutions, suspensions or
emulsions of the active compound of the formula I or its physiologically
tolerable salts in a pharmaceutically innocuous solvent, such as, in
particular, ethanol or water, or a mixture of such solvents. If required,
the formulation can also additionally contain other pharmaceutical
excipients such as surfactants, emulsifiers and stabilizers, and a
propellant. Such a preparation customarily contains the active compound
in a concentration of approximately 0.1 to 10, in particular of
approximately 0.3 to 3, percent by weight.

[0027]The dose of the active compound of the formula I or of the
physiologically tolerable salts thereof to be administered depends on the
individual case and is to be adapted to the conditions of the individual
case as customary for an optimum action. Thus, it depends, of course, on
the frequency of administration but also on the nature and severity of
the illness to be treated and on the sex, age, weight and individual
responsiveness of the human or animal to be treated and on whether the
therapy is to be acute or chronic or prophylaxis is to be carried out.
Customarily, the daily dose of the compound of the formula I in the case
of administration to a patient weighing approximately 75 kg is 0.01 mg/kg
of bodyweight to 100 mg/kg of bodyweight, preferably 0.1 mg/kg of
bodyweight to 20 mg/kg of bodyweight. The dose can be administered in the
form of an individual dose or divided into a number of, for example two,
three or four, individual doses. In particular in the treatment of acute
cases of cardiac arrhythmias, for example in an intensive care unit,
parenteral administration by injection or infusion, for example by an
intravenous continuous infusion, can also be advantageous.

[0028]20 g (188 mmol) of sodium carbonate were added to a suspension of 20
g (146 mmol) of 2-aminobenzoic acid in 250 ml of water. 11.4 g (72.8
mmol) of butylsulfonyl chloride were then added dropwise and the reaction
mixture was stirred at room temperature for 2 days. It was acidified with
concentrated hydrochloric acid, stirred at room temperature for 3 hours
and the precipitated product was filtered off with suction. After drying
in vacuo, 9.6 g of 2-(butyl-1-sulfonylamino)benzoic acid were obtained.

b) 1-(6-Methoxypyridin-3-yl)propylamine

Method 1

[0029]3 ml (23.2 mmol) of 5-bromo-2-methoxypyridine were added at
-70° C. to a solution of 10.2 ml of n-butyllithium (2.5 M solution
in hexane; 25.5 mmol) in 50 ml of diethyl ether. After 10 min, 1.4 ml
(19.5 mmol) of propionitrile were added. After 2 hours at -70° C.,
the reaction mixture was slowly allowed to come to room temperature. 2.2
g of sodium sulfate decahydrate were then added and the mixture was
allowed to stir for 1 hour. After subsequent addition of 5 g of magnesium
sulfate, the salts were filtered off after brief stirring and the
filtrate was concentrated. The residue was dissolved in 70 ml of methanol
and 1.1 g (28 mmol) of sodium borohydride were added at 0° C.
After stirring overnight, the reaction mixture was adjusted to pH 2 using
concentrated hydrochloric acid and concentrated on a rotary evaporator.
The residue was treated with 10 ml of water and extracted once with
diethyl ether. The aqueous phase was then saturated with sodium hydrogen
carbonate, concentrated in vacuo and the residue was extracted with ethyl
acetate. After drying and concentrating the ethyl acetate extracts, 1.4 g
of racemic 1-(6-methoxypyridin-3-yl)propylamine were obtained.

[0031]First, 0.45 g of 1(S)-(6-methoxypyridin-3-yl)propylamine was eluted
at a retention time of 18.4 min. 0.42 g of
1(R)-(6-methoxypyridin-3-yl)propyl-amine was then obtained at a retention
time of 21.0 min.

Method 2

[0032]170 ml (170 mmol) of a 1 M solution of ethylmagnesium bromide in
tetrahydrofuran were added dropwise at 0° C. under argon in the
course of 30 minutes to a solution of 20 g (150 mmol) of
6-methoxynicotinonitrile and 0.62 g (3.3 mmol) of copper(I) iodide in 125
ml of anhydrous tetrahydrofuran. After 30 minutes, the reaction mixture
was allowed to come to room temperature and was stirred for a further 3
h. 200 ml of methanol were then added dropwise at 5-10° C. and
11.3 g (299 mmol) of sodium borohydride were then added in portions.
After stirring overnight at room temperature, 300 ml of water were added
and the mixture was extracted 3 times using 250 ml of ethyl acetate each
time. The organic phase was dried over magnesium sulfate, then
concentrated and the residue was purified by chromatography. 5.5 g of
racemic 1-(6-methoxypyridin-3-yl)propylamine were obtained.

[0033]4.4.9 (32.7 mmol) of 1-hydroxy-1H-benzotriazole and 6.3 g (32.7
mmol) of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride
were added to a solution of 8.0 g (31.1 mmol) of
2-(butyl-1-sulfonylamino)benzoic acid in 250 ml of tetrahydrofuran and
the reaction mixture was stirred for 90 min. A solution of 5.4 g (32.7
mmol) of racemic 1-(6-methoxypyridin-3-yl)propyl-amine in 20 ml of
tetrahydrofuran was then added dropwise and the mixture was stirred
overnight. The reaction mixture was treated with 250 ml of water and
extracted with 300 ml of ethyl acetate. The organic phase was extracted 5
times with 100 ml of saturated sodium hydrogen carbonate solution each
time and then dried over magnesium sulfate. 9.0 g of
2-(butyl-1-sulfonylamino)-N-[1-(6-methoxypyridin-3-yl)propyl]benzamide
were obtained.

[0035]First, 4.0 g of
2-(butyl-1-sulfonylamino)-N-[1(R)-(6-methoxypyridin-3-yl)-propyl]benzamid-
e were eluted at a retention time of 5.9 min. After a mixed fraction, 3.0
g of 2-(butyl-1-sulfonylamino)-N-[1(S)-(6-methoxypyridin-3-yl)-propyl]ben-
zamide were then obtained at a retention time of 7.2 min.

Method 2

[0036]0.9 g of
2-(butyl-1-sulfonylamino)-N-[1(R)-(6-methoxypyridin-3-yl)propyl]-benzamid-
e was obtained from 0.41 g (2.46 mmol) of
1(R)-(6-methoxy-pyridin-3-yl)propylamine and 0.64 g (2.47 mmol) of
2-(butyl-1-sulfonylamino)-benzoic acid by coupling in the presence of
1-hydroxy-1H-benzotriazole and
N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride analogously
to method 1.

d) 2-(Butyl-1-sulfonylamino)-N-[1(R)-(6-methoxypyridin-3-yl)propyl]benzami-
de

[0037]2 g of the
2-(butyl-1-sulfonylamino)-N-[1(R)-(6-methoxypyridin-3-yl)propyl]-benzamid-
e obtained according to method 1 or method 2 were dissolved in 9 ml of
isopropanol in the presence of heat, then 8 ml of warm water were added
and the reaction mixture was allowed to cool slowly overnight. After
filtering off with suction at 0° C., 1.5 g of
2-(butyl-1-sulfonylamino)-N-[1(R)-(6-methoxypyridin-3-yl)propyl]benzamide
were obtained as colorless needle-shaped crystals; melting point
97° C. The absolute configuration was confirmed from suitable
monocrystals by x-ray structural analysis.

Pharmacological Investigations

[0038]Kv1.5 channels from humans were expressed in Xenopus oocytes. For
this, oocytes were first isolated from Xenopus laevis and defolliculated.
RNA encoding Kv1.5 and synthesized in vitro was then injected into these
oocytes. After Kv1.5 protein expression for 1-7 days, Kv1.5 currents were
measured at the oocytes using the two microelectrode voltage clamp
technique. The Kv1.5 channels were in this case as a rule activated using
voltage jumps to 0 mV and 40 mV lasting 500 ms. The bath was rinsed using
a solution of the following composition: NaCl 96 mM, KCl 2 mM, CaCl2
1.8 mM, MgCl2 1 mM, HEPES 5 mM (titrated to pH 7.4 using NaOH).
These experiments were carried out at room temperature. The following
were employed for data acquisition and analysis: Geneclamp amplifier
(Axon Instruments, Foster City, USA) and MacLab D/A converter and
software (ADInstruments, Castle Hill, Australia). The substances
according to the invention were tested by adding them to the bath
solution in different concentrations. The effects of the substances were
calculated as percentage inhibition of the Kv1.5 control current which
was obtained when no substance was added to the solution. The data were
then extrapolated using the Hill equation in order to determine the
inhibitory concentrations IC50 for the respective substances.

[0039]In this manner, the following IC50 values were determined for
the compounds listed below:
[0040]2-(Butyl-1-sulfonylamino)-N-[1-(6-methoxypyridin-3-yl)propyl]benzam-
ide: IC50=2.4 μM
[0041]2-(Butyl-1-sulfonylamino)-N-[1(R)-(6-methoxypyridin-3-yl)propyl]ben-
zamide of the formula I:

[0043]Investigation of the refractory period and the left-atrial
vulnerability in the pig

[0044]The two enantiomers
2-(butyl-1-sulfonylamino)-N-[1(R)-(6-methoxypyridin-3-yl)propyl]benzamide
of the formula I and 2-(butyl-1-sulfonylamino)-N-[1
(S)-(6-methoxypyridin-3-yl)propyl]benzamide were investigated and
compared for prolongation of the refractory period and antiarrhythmic
activity on the atrium of the anesthetized pig. In the course of this,
the refractory period of the left atrium was determined and the
antiarrhythmic activity was recorded as described in the literature
(Knobloch et al. 2002. Naunyn-Schmiedberg's Arch. Pharmacol. 366;
482-487). The anti-arrhythmic action relates here to the inhibition of
the occurrence of episodes of arrhythmias which are induced by a
prematurely placed extra-stimulus (S2) in the left atrium (=left-atrial
vulnerability).

[0045]A comparison of the action of
2-(butyl-1-sulfonylamino)-N-[1(R)-(6-methoxypyridin-3-yl)propyl]benzamide
of the formula I and
2-(butyl-1-sulfonylamino)-N-[1(S)-(6-methoxypyridin-3-yl)propyl]benzamide
on the refractory period of the left atrium and antiarrhythmic activity
in the anesthetized pig after a bolus administration of 3 mg/kg is shown
in table 1. The refractory period values are stated in percent of the
basal values 10 minutes after injection. Mean values for the refractory
periods are shown from three rates (150, 200 and 250/min). From the
results compiled in table 1, it is seen that the R enantiomer causes a
markedly greater prolongation of the refractory period than the S
enantiomer. By using the R enantiomer, it was possible to prevent 73.9%
of the induced arrhythmias, while when using the S enantiomer the
occurrence of arrhythmias was inhibited only by 27%.

[0046]By repeated measurement after substance administration, the duration
of action of a substance on the refractory period can be determined in
this experimental procedure. The R enantiomer was infused intravenously
over the course of 100 minutes in a dose of 1 mg/kg and the
pharmacological action was determined over the course of 280 minutes. As
shown in FIG. 1,
2-(butyl-1-sulfonylamino)-N-[1(R)-(6-methoxypyridin-3-yl)propyl]benzamide
led to a long-lasting action on the left-atrial refractory period, which
also continued unchanged for 180 minutes after ending the infusion.

DESCRIPTION OF THE DRAWINGS

[0047]The following captions and markings were made in the drawing:

[0048]FIG. 1: duration of action on the refractory period of the left
atrium of 2-(butyl-1-sulfonylamino)-N-[1(R)-(6-methoxypyridin-3-yl)propyl-
]benzamide, 1 mg/kg as an infusion over the course of 100 minutes
intravenously